Dose-dependent incidence of agranulocytosis in patients treated with methimazole and propylthiouracil.

Agranulocytosis is a serious adverse effect of methimazole (MMI) and propylthiouracil (PTU), and although there have been reports suggesting a dose-dependent incidence in relation to both drugs, the evidence has not been conclusive. The objective of our study was to determine whether the incidences of agranulocytosis induced by MMI and PTU exhibit dose-dependency. The subjects were 27,784 patients with untreated Graves' disease, 22,993 of whom were on an antithyroid drug treatment regimen for more than 90 days. Within this subset, 18,259 patients had been treated with MMI, and 4,734 had been treated with PTU. The incidence of agranulocytosis according to dose in the MMI group was 0.13% at 10 mg/day, 0.20% at 15 mg/day, 0.32% at 20 mg/day, and 0.47% at 30 mg/day, revealing a significant dose-dependent increase. In the PTU group, there were 0 cases of agranulocytosis at doses of 125 mg/day and below, 0.33% at 150 mg/day, 0.31% at 200 mg/day, and 0.81% at 300 mg/day, also revealing a significant dose-dependent increase. The incidence of agranulocytosis at MMI 15 mg and PTU 300 mg, i.e., at the same potency in terms of hormone synthesis inhibition, was 0.20% and 0.81%, respectively, and significantly higher in the PTU group. Our findings confirm a dose-dependent increase in the incidence of agranulocytosis with both drugs, but that at comparable thyroid hormone synthesis inhibitory doses PTU has a considerably higher propensity to induce agranulocytosis than MMI does.

Apolipoprotein A2 isoforms associated with exocrine pancreatic insufficiency in early chronic pancreatitis.

BACKGROUND AND AIM: Apolipoprotein A2 (apoA2) isoforms have been reported to undergo the aberrant processing in pancreatic cancer and pancreatic risk populations compared with that in healthy subjects. This study aimed to clarify whether apoA2 isoforms were as useful as N-benzoyl-p-aminobenzoic acid (BT-PABA) test for exocrine pancreatic dysfunction markers in patients with early chronic pancreatitis (ECP). METHODS: Fifty consecutive patients with functional dyspepsia with pancreatic enzyme abnormalities (FD-P) (n = 18), with ECP (n = 20), and asymptomatic patients with pancreatic enzyme abnormalities (AP-P) (n = 12) based on the Rome IV classification and the Japan Pancreatic Association were enrolled in this study. The enrolled patients were evaluated using endoscopic ultrasonography and endoscopic ultrasonography elastography. Five pancreatic enzymes were estimated. Pancreatic exocrine function was analyzed using the BT-PABA test. Lighter and heavier apoA2 isoforms, AT and ATQ levels were measured by enzyme-linked immunosorbent assay methods. RESULTS: There were no significant differences in clinical characteristics such as age, gender, body mass index, alcohol consumption and smoking among patients with AP-P, FD-P, and ECP. The BT-PABA test and lighter apoA2 isoform, AT level in the enrolled patients had a significant correlation (P < 0.01). The BT-PABA test in patients with ECP was significantly lower (P = 0.04) than that in AP-P. ApoA2-AT level in patients with ECP was lower than that in AP-P, albeit, insignificantly. Interestingly, apo A2-AT level was significantly (P = 0.041) associated with exocrine pancreatic insufficiency by multiple logistic regression analysis. CONCLUSIONS: ApoA2-AT level is a useful tool to evaluate exocrine pancreatic insufficiency in the early stage of chronic pancreatitis.

Clinical features of moyamoya disease with Graves' disease: a retrospective study of 394,422 patients with thyroid disease.

Graves' disease has been reported to affect the clinical features of moyamoya disease (MMD), an occlusion of the circle of Willis. This study aimed to clarify the characteristics of MMD in patients with Graves' disease. This was a single-center, retrospective study. The prevalence and clinical features of MMD patients among all patients with thyroid disease who visited Ito Hospital from January 2005 to December 2019 were evaluated. The relationship between MMD and hyperthyroidism was analyzed in new-onset Graves' disease patients during the same period. Of all 394,422 patients with thyroid disease, 88,180 had Graves' disease, and 40 had MMD with Graves' disease, i.e., the prevalence was 45.36 per 100,000 patients with Graves' disease (0.0454%). The median age at onset of MMD was 39 years (interquartile range, 31-54 years), with a male to female ratio of 1:12. The most common time that MMD was diagnosed was within 1 year after the onset of Graves' disease, in 9 of 40 patients (22.5%), and 19 of 40 patients (47.5%) underwent bypass surgery for MMD. In MMD with Graves' disease, headache was the most frequent symptom, and ischemic types of stroke and bilateral lesions were common. Of 23,347 patients with new-onset Graves' disease, 7 were diagnosed with MMD and the incidence of MMD was 5.94 patients per 100,000 person-years. Most patients developed MMD symptoms during hyperthyroidism. Although MMD is a rare condition, it should be noted that it can occur with Graves' disease.

Establishment of reference intervals for fT3, fT4, and TSH levels in Japanese children and adolescents.

The present study aimed to establish new reference intervals (RIs) for serum free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH) levels in Japanese children and adolescents aged 4 to 19 years. A total of 2,036 (1,611 girls, 425 boys) participants were included over a 17-year period; they all tested negative for antithyroid antibodies (TgAb, TPOAb) and were found to have no abnormalities on ultrasonography. RIs were determined by nonparametric methods. The results showed that serum fT3 was significantly higher in the 4-15-year-olds than in the 19-year-olds. The serum fT4 was significantly higher in the 4-10-year-olds than in the 19-year-olds. The serum TSH was significantly higher in the 4-12-year-olds than in the 19-year-olds. All of them gradually decreased with age to approximate the adult levels. The upper limit of TSH was lower in those aged 13 to 19 years than in adults. The differences were examined by sex. The serum fT3 was significantly higher in boys than in girls between the ages of 11 and 19 years. The serum fT4 was significantly higher in boys than in girls between the ages of 16 and 19 years. There did not seem to be any sex difference in those under 10 years of age. In conclusion, serum fT3, fT4, and TSH levels in children and adolescents differ from those in adults. It is important to evaluate thyroid function using the new RIs that are appropriate for chronological age.

Incidence and risk factors for Graves' orbitopathy in patients who underwent anti-inflammatory and immunosuppressive treatment during medical treatment for Graves' disease: investigation of 1,553 cases with newly diagnosed Graves' disease and proposal of a predictive score.

Appropriate administration of anti-inflammatory and immunosuppressive treatment (AIIST) is important for patients with Graves' orbitopathy (GO). This study aimed to clarify the incidence and risk factors for GO treated with AIIST and propose a predictive score, among newly diagnosed Graves' disease (GD) patients in Japan. A total of 1,553 GD patients who were newly diagnosed during the year 2011 were investigated. AIIST included local and/or systemic glucocorticoid administration and retrobulbar irradiation. A multivariable Cox proportional hazards model was used to investigate the risk factors for GO underwent AIIST during medical treatment, including at diagnosis, of GD. Then, a GO score was created by summing each point assigned to risk factors based on their coefficient obtained in the Cox model. AIIST was administered to 107 patients (6.9%). The risk factors and hazard ratios for GO underwent AIIST were: age (per 10 years), 1.32 (95% confidence interval: 1.16-1.50), p < 0.0001; TSH binding inhibitory immunoglobulin (TBII) (per 10 IU/L), 1.33 (1.15-1.54), p = 0.0001; and thyroglobulin antibody (TgAb) negativity, 2.98 (1.96-4.59), p < 0.0001. The GO score, ranging from 0 to 8 points, showed moderate performance (area under the curve: 0.71, cut-off value: 5 points, sensitivity: 0.76, specificity: 0.59, positive predictive value: 0.12, negative predictive value: 0.97). AIIST was performed for patients with active manifestations of GO in 6.9% of newly diagnosed GD patients. The risk factors for GO underwent AIIST were higher age, higher TBII, and TgAb negativity. The GO score based on these factors may be useful in managing GO.

Radioiodine uptake after monotherapy with potassium iodide in patients with Graves' disease.

The effect of potassium iodide (KI) on radioiodine uptake (RAIU) before radioisotope therapy in Graves' disease (GD) patients was investigated. A total of 82 patients who had been treated with KI monotherapy before 24-hour RAIU (24 h RAIU) were evaluated and 354 of those who had been treated with thiamazole (MMI) monotherapy were extracted from the 1,130 GD patients who were identified as having had appropriate iodine restriction based on urinary iodine excretion. Urinary iodine excretion (UIE) <200 µg/day was confirmed in all subjects. Propensity score-matching was performed to identify the difference in 24 h RAIU between the KI group and the MMI group. In addition, multiple regression analysis was performed to evaluate related to 24 h RAIU. Propensity score-matching resulted in 57 matched patients in each group. After matching, 24 h RAIU was still significantly lower in the KI group than in the MMI group (median 53% (interquartile range 47-61%) vs. 63% (56-66%); p = 0.001). In addition, KI monotherapy was weakly negatively correlated with 24 h RAIU, whereas the female sex and FT3 were very weakly positively correlated on multiple regression analysis. The results suggest that KI monotherapy likely suppressed 24 h RAIU more than MMI monotherapy in GD patients with appropriate iodine restriction, given the difference in the mechanism of hormone suppression.

Prediction model of Graves' disease in general clinical practice based on complete blood count and biochemistry profile.

Although untreated Graves' disease (GD) is associated with a higher risk of cardiac complications and mortality, there is no well-established way to predict the onset of thyrotoxicosis in clinical practice. The aim of this study was to identify important variables that will make it possible to predict GD and thyrotoxicosis (GD + painless thyroiditis (PT)) by using a machine-learning-based model based on complete blood count and standard biochemistry profile data. We identified 19,335 newly diagnosed GD patients, 3,267 PT patients, and 4,159 subjects without any thyroid disease. We built a GD prediction model based on information obtained from subjects regarding sex, age, a complete blood count, and a standard biochemistry profile. We built the model in the training set and evaluated the performance of the model in the test set by using the artificial intelligence software Prediction One. Our machine learning-based model showed high discriminative ability to predict GD in the test set (area under the curve [AUC] 0.99). The main contributing factors to predict GD included age and serum creatinine, total cholesterol, alkaline phosphatase, and total protein levels. We still found high discriminative ability even when we restricted the variables to these five most contributory factors in our prediction model (AUC 0.97) built by using artificial intelligence software showed high GD prediction ability based on information regarding only five factors.

A case of macro-TSH consisting of IgA-bound TSH.

An asymptomatic, 68-year-old Japanese man visited our hospital for further examination of subclinical hypothyroidism. At the first visit, the serum TSH level was markedly elevated (36.6 µIU/mL), but the serum level of free T4 was within the reference interval. Thyroid dysfunction due to dietary iodine excess was initially suspected. However, even after iodine restriction, his thyroid function tests were the same as at the first visit, which suggested false elevation of the TSH level. The TSH levels were compared among three different measurement systems, which showed a similar tendency of TSH elevation above the reference interval, but the different TSH elevation levels among the measurement methods suggested the existence of some interfering substance. Neither serial dilution of the patient's serum nor polyethylene glycol and protein G precipitation tests showed any significant changes in the recovery rate. IgG-bound macro-TSH was ruled out. The TSH peak on gel filtration chromatography was located at a molecular size greater than IgA, which suggested the presence of IgA-bound TSH. After precipitation with Jacalin, which binds specifically to IgA, the TSH level decreased from 30.7 µIU/mL to 2.01 µIU/mL, within the reference interval. Thus, IgA-bound macro-TSH was identified. Macro-TSH is a rare condition in which an immunoglobulin-bound, high-molecular-weight form of TSH results in a false elevation of the serum TSH level. When there is a discrepancy between the results of thyroid function tests and clinical symptoms, and macro-TSH is suspected, it is necessary to know that not only IgG-bound TSH but also IgA-bound TSH could be the cause.

TRAb elevations occurred even in the third trimester; a case of a mother of a child with neonatal thyroid dysfunction, who received radioactive iodine therapy for Graves' disease.

Activity of Graves' disease (GD) is known to improve during gestation, as values of thyrotropin (TSH) receptor antibody (TRAb) also improve. However, the risk of neonatal hyperthyroidism increases when maternal TRAb values are high in the second to third trimester. A 29-year-old woman who had undergone radioactive iodine (RAI) therapy for GD 10 years earlier visited our hospital at 17 weeks of gestation, showing subclinical hypothyroidism and a positive TRAb value of 2.6 IU/L (reference range, <2.0 IU/L). Thyroid hormone replacement therapy was commenced and thyroid function normalized within 4 weeks, although TRAb was elevated at the time (3.8 IU/L). Prenatal check-up showed normal growth development and no irregularities. At 29 weeks of gestation, serum TRAb was extremely elevated, up to 16.8 IU/L. Since the risk of neonatal hyperthyroidism was of great concern, delivery was planned at an advanced-care medical center. At 38 weeks 5 days of gestation, she delivered a female neonate without any complications, although blood testing of the neonate showed subclinical hyperthyroidism with positive TRAb and TSH receptor stimulating antibody (TSAb). According to the American Thyroid Association guidelines, the TRAb value should be checked in the third trimester if mothers show a TRAb elevation between the initial visit after pregnancy and 18-22 weeks of gestation. However, if the mother has a history of RAI therapy for GD, regardless of thyroid function during gestation, the possibility of TRAb values elevating over time even years after the definitive therapy must be considered.

Therapeutic efficacy and limitations of potassium iodide for patients newly diagnosed with Graves' disease.

The efficacy of potassium iodide (KI) for Graves' disease (GD) has been reported, although few clinical reports have examined the long-term efficacy of treatment. The objective of this study was to investigate the efficacy and limitations of KI treatment for GD. This study enrolled patients newly diagnosed with mild GD, defined as free thyroxine (FT4) <5.0 ng/dL, between July 2014 and June 2016. KI was started at a dose of 50 mg/day, and if FT4 values did not decrease after initiation of treatment, doses were increased to 100 mg/day. Patients for whom thyroid hormone levels could not be controlled with KI at 100 mg/day were regarded as non-responders. Of the 122 patients (13 males, 109 females) included in this study, 71 (58.2%) responded to KI therapy. The remaining 51 patients (41.8%) were non-responders. The median duration required to judge non-responsiveness was 5.9 months. Multiple logistic regression analysis performed on parameters measured at the initial visit indicated FT4 (odds ratio (OR) 2.19, 95% confidence interval (CI) 1.28-3.75; p = 0.0007) and male sex (OR 3.58, 95%CI 1.04-12.3; p = 0.04) were significantly associated with KI responsiveness. Receiver operating characteristic (ROC) curve analysis of the relationship between FT4 and KI responsiveness indicated an FT4 cut-off of 2.76 ng/dL was optimal for differentiating between responders and non-responders. KI therapy was effective and safe for about 60% of patients with mild GD.

The characteristics of osteoporotic patients in Graves' disease patients newly diagnosed after menopause: a prospective observational study.

Overt hyperthyroidism is associated with reduced bone density. The extent of restoration of reduced bone density caused by hyperthyroidism in postmenopausal Graves' disease (GD) patients has not fully been investigated. We examined 85 newly diagnosed postmenopausal GD patients, and we measured their serum thyroid hormone levels as well as their bone turnover marker levels and the bone mineral density (BMD) of their lumbar spine (LS), both femoral necks (FN), and left distal radius (DR). We prospectively observed the patients for changes in BMD and bone turnover marker levels during a 24-month period after euthyroidism had been established by ATD treatment. The median age of the subjects was 57 years old (range: 50 to 79). 46 (54.1%) patients had osteoporosis. 42 of the 46 osteoporosis patients had low BMD in the DR. The patients with osteoporosis were significantly older, had a significantly lower BMI, and had significantly higher bone turnover marker levels compared to the normal BMD patients. The best predictor of the BMD in the DR was BMD in the FN (ß = 0.40, p < 0.0001). A total of 42 patients were followed up for 24 months after attainment of euthyroidism, and 19 of them were osteoporosis at the first visit. The BMD of the 19 osteoporotic patients had increased by 4.9% in the LS, 11.9% in the FN, and 9.3% in the DR at 24 months. After maintaining a euthyroid state for 24 months by means of ATD treatment, 26% of the osteoporotic patients had recovered from osteoporosis.

Large-Scale Identification of N-Glycan Glycoproteins Carrying Lewis x and Site-Specific N-Glycan Alterations in Fut9 Knockout Mice.

The Lewis x (Le(x)) structure (Galß1-4(Fucα1-3)GlcNAc-R) is a carbohydrate epitope comprising the stage-specific embryonic antigen-1 (SSEA-1) and CD15, and it is synthesized by α1,3-fucosyltransferase 9 (Fut9). Fut9 is expressed specifically in the stomach, kidney, brain, and in leukocytes, suggesting a specific function in these tissues. In this study, the N-linked glycan mass spectrometry profile of wild-type mouse kidney glycoproteins revealed the presence of abundant terminal fucoses, which were lost following knockout of the Fut9 gene; the terminal fucose was therefore concluded to be Le(x). These results suggested that Le(x) presence is widespread rather than being limited to specific proteins. We endeavored to comprehensively identify the Le(x) carriers in the mouse kidney. Glycopeptides carrying fucosylated glycans were collected by Aleuria aurantia lectin (AAL) affinity chromatography from kidney homogenates of wild-type and Fut9 knockout mice. The site-specific N-glycomes on the glycopeptides were subsequently analyzed by adopting a new glycoproteomic technology composed of dissociation-independent assignment of glycopeptide signals and accurate mass-based prediction of the N-glycome on the glycopeptides. Our analyses demonstrated that 24/32 glycoproteins contained the Le(x) N-glycan structure in wild-type kidney; of these, Le(x) was lost from 21 in the knockout mice. This is the first report of large-scale identification of Le(x)-carrying glycoproteins from a native sample based on the site-specific glycome analysis.

Serum human chorionic gonadotropin levels and thyroid hormone levels in gestational transient thyrotoxicosis: Is the serum hCG level useful for differentiating between active Graves' disease and GTT?

Gestational transient thyrotoxicosis (GTT) is defined as transient thyrotoxicosis caused by the stimulating effect of human chorionic gonadotropin (hCG) during pregnancy. We attempted to identify the serum hCG level that causes GTT, and we compared the serum hCG levels and thyroid hormone levels of GTT patients according to whether they had a background of thyroid disease. We also evaluated serum hCG as a parameter for differentiating between active Graves' disease (GD) and GTT. We reviewed the 135 cases of pregnant women who came to our hospital to be evaluated for thyrotoxicosis during their 7th to 14th week of pregnancy, and their serum hCG level was measured at that time. Among the 135 pregnant women with thyrotoxicosis; 103 of the women had GTT, and the other 32 women had active GD. There were no correlations between their serum hCG levels and free thyroid hormone levels. There were no significant differences in thyroid hormone levels or hCG levels among the GTT groups with different thyroid disease backgrounds; i.e., the GTT group without thyroid disease, GTT group with chronic thyroiditis, GTT group with non-functioning thyroid nodules, and GTT group with GD in remission. The serum hCG level of the GTT group was significantly higher than in the active GD group, but it was not a good parameter for differentiating between the two groups. The FT3/FT4 ratio of the active GD was significantly higher than in GTT group, and was a better parameter for differentiation.

Changes in pediatric thyroid sonograms in or nearby the Kanto region before and after the accident at the Fukushima Daiichi nuclear power plant.

Following the accident at the Fukushima Daiichi Nuclear Power Station which occurred on March 11, 2011 due to the Eastern Japan Great Earthquake (the Accident), there have been concerns over elevation of the risk of thyroid cancer among children due to internal exposure to radioactive iodine. In Fukushima Prefecture, screening of children with thyroid ultrasonography has been carried out, yielding numerous findings, suggesting a possible influence from the Accident. We report thyroid ultrasonographic findings, used by similar device at Fukushima Prefecture's study, at Ito-hospital. Of the 2721 children aged 15 or less who visited our hospital between January 2005 and March 2013, 1214 children (330 boys and 884 girls; median age, 12; range of age, 4-15) were covered by evaluation of thyroid ultrasonographic findings, excluding children known in advance to have thyroid disease on the basis of disease history, palpation and blood tests. Among these 1214 children, 709 children (58.4%) were found cysts (≤ 5 mm in 665 cases) by ultrasonography, 43 children (3.5%) were found nodules (≤ 5 mm in 18 cases) and 9 children (5.2%) were found an intrathyroid ectopic thymus. Analysis of the data before and after the Accident using the same device, involving age adjustment on the basis of the standard population in 2010, showed no difference in the incidence rate of cysts or nodules. In children examined, the incidence rate of cyst formation (particularly ≤ 5 mm) was higher, and there was no difference in the incidence rate of cysts or nodules between the pre- and post-accident period.

Limb-Clasping Response in NMDA Receptor Palmitoylation-Deficient Mice.

Proper regulation of N-methyl-D-aspartate-type glutamate receptor (NMDA receptor) expression is responsible for excitatory synaptic functions in the mammalian brain. NMDA receptor dysfunction can cause various neuropsychiatric disorders and neurodegenerative diseases. Posttranslational protein S-palmitoylation, the covalent attachment of palmitic acid to intracellular cysteine residues via thioester bonds, occurs in the carboxyl terminus of GluN2B, which is the major regulatory NMDA receptor subunit. Mutations of three palmitoylatable cysteine residues in the membrane-proximal cluster of GluN2B to non-palmitoylatable serine (3CS) lead to the dephosphorylation of GluN2B Tyr1472 in the hippocampus and cerebral cortex, inducing a reduction in the surface expression of GluN2B-containig NMDA receptors. Furthermore, adult GluN2B 3CS homozygous mice demonstrated a definite clasping response without abnormalities in the gross brain structure, other neurological reflexes, or expression levels of synaptic proteins in the cerebrum. This behavioral disorder, observed in the GluN2B 3CS knock-in mice, indicated that complex higher brain functions are coordinated through the palmitoylation-dependent regulation of NMDA receptors in excitatory synapses.

Determination of Capillary Blood TSH and Free Thyroxine Levels Using Digital Immunoassay.

Background: The remote performance of thyroid function blood tests is complicated because it requires blood collection. Objective: To compare TSH and free thyroxine (FT4) levels between capillary and venous blood and assess the adequacy of measuring each value in capillary blood. Methods: This prospective intervention study was conducted at Ito Hospital and was based on the clinical research method. The participants were 5 healthy female volunteers and 50 patients (41 females and 9 males) between the ages of 23 and 81 years. To measure TSH and FT4 levels in capillary and venous blood, a digital immunoassay (d-IA) method capable of measuring trace samples was used. Chemiluminescence measurements were used as controls. Values obtained for each assay system were compared using Spearman's correlation analysis. Capillary blood was collected using an autologous device (TAP II; not approved in Japan). Results: Capillary plasma volume obtained using TAP II was 125 µL or more in 26 cases, 25 µL to 124 µL in 24 cases, and less than 25 µL in 5 cases. Strong correlations were noted in the TSH and FT4 levels between capillary and venous blood, with correlation coefficients of rs = 0.99 and rs = 0.97, respectively. Conclusion: Capillary TSH and FT4 levels strongly correlate with venous blood values. Trace samples can be used in high-precision d-IA methods. These results may promote telemedicine in assessing thyroid function.

An Evaluation of the Efficacy of Machine Learning in Predicting Thyrotoxicosis and Hypothyroidism: A Comparative Assessment of Biochemical Test Parameters Used in Different Health Checkups.

Objective This study assessed the efficacy of machine learning in predicting thyrotoxicosis and hypothyroidism [thyroid-stimulating hormone >10.0 mIU/L] by leveraging age and sex as variables and integrating biochemical test parameters used by the Japan Society of Health Evaluation and Promotion (JHEP) and the Japan Society of Ningen Dock (JND). Methods Our study included 20,653 untreated patients with Graves' disease, 3,435 untreated patients with painless thyroiditis, 4,266 healthy individuals, and 18,937 untreated patients with Hashimoto's thyroiditis. Machine learning was conducted using Prediction One on three distinct datasets: the Ito dataset (age, sex, and 30 blood tests and biochemical test data), the JHEP dataset (age, sex, and total protein,total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γGTP), alkaline phosphatase, creatinine (CRE), uric acid (UA), and T-Cho test data), and the JND dataset (age, sex, and AST, ALT, γGTP, CRE, and UA test data). Results The results for distinguishing thyrotoxicosis patients from the healthy control group showed that the JHEP dataset yielded substantial discriminative capacity with an area under the curve (AUC) of 0.966, sensitivity of 92.2%, specificity of 89.1%, and accuracy of 91.7%. The JND dataset displayed similar robustness, with an AUC of 0.948, sensitivity of 92.0%, specificity of 81.3%, and accuracy of 90.4%. Differentiating hypothyroid patients from the healthy control group yielded similarly robust performances, with the JHEP dataset yielding AUC, sensitivity, specificity, and accuracy values of 0.864, 84.2%, 72.1%, and 77.4%, respectively, and the JND dataset yielding values of 0.840, 83.2%, 67.2%, and 74.3%, respectively. Conclusion Machine learning is a potent screening tool for thyrotoxicosis and hypothyroidism.

Subacute thyroiditis during pregnancy: clinical characteristics of seven cases.

Objective: There are few reports of subacute thyroiditis (SAT) during pregnancy. This study aimed to clarify the clinical characteristics of SAT in pregnant patients. Methods and results: Seven patients diagnosed with SAT during pregnancy at our institution from January 2004 to December 2021 were identified, and their clinical findings were retrospectively examined. At SAT diagnosis, the median age was 34 (range: 31-42) years, the median duration of pregnancy was 5 (4-24) weeks, and all patients had neck pain but no fever. On laboratory examination, median (range) free thyroxine, free triiodothyronine, and C-reactive protein levels were 2.66 (1.14-7.77) ng/dL, 7.1 (3.3-16.1) pg/mL, and 2.22 (0.42-5.79) mg/dL, respectively, and all patients had a hypoechoic lesion of the thyroid gland. Three patients (43%) were treated with steroids, and three patients (43%) received replacement therapy with levothyroxine for hypothyroidism following destructive thyroiditis. There were no pregnancy complications in any of the cases. These seven patients (pregnancy group) were compared with 217 non-pregnant female patients (non-pregnancy group) aged 31 to 42 years who were diagnosed with SAT at our institution from 2016 to 2019. The frequency of body temperatures above 37°C was lower in the pregnancy group than in the non-pregnancy group (0% vs 65%). Conclusion: Patients who develop SAT during pregnancy may have less fever than non-pregnant patients with SAT. There were no pregnancy complications in the pregnancy group in this study. This suggests that adverse pregnancy outcomes may be avoided by the appropriate management of SAT, including hypothyroidism after destructive thyroiditis.

Exacerbation of Thyroid Eye Disease and Dysthyroid Optic Neuropathy During Pregnancy: A Case Report.

A 37-year-old, never-smoker, pregnant woman diagnosed with Graves' disease who had stable thyroid eye disease (TED) before pregnancy presented with aggravated proptosis and eyelid swelling at 13 weeks of pregnancy. Despite the administration of local triamcinolone and 3 cycles of corticosteroid pulse therapy from 25 to 28 weeks, the patient's visual acuity decline necessitated postpartum orbital decompression surgery. Although TSH receptor antibody (TRAb) levels decreased during the mid- to late term of pregnancy, the TED worsened. This finding suggests that factors other than anti-TSH receptor antibodies may have a significant effect on disease severity.

Lack of lacto/neolacto-glycolipids enhances the formation of glycolipid-enriched microdomains, facilitating B cell activation.

In a previous study, we demonstrated that beta1,3-N-acetylglucosaminyltransferase 5 (B3gnt5) is a lactotriaosylceramide (Lc(3)Cer) synthase that synthesizes a precursor structure for lacto/neolacto-series glycosphingolipids (GSLs) in in vitro experiments. Here, we generated B3gnt5-deficient (B3gnt5(-/-)) mice to investigate the in vivo biological functions of lacto/neolacto-series GSLs. In biochemical analyses, lacto/neolacto-series GSLs were confirmed to be absent and no Lc(3)Cer synthase activity was detected in the tissues of these mice. These results demonstrate that beta3GnT5 is the sole enzyme synthesizing Lc(3)Cer in vivo. Ganglioside GM1, known as a glycosphingolipid-enriched microdomain (GEM) marker, was found to be up-regulated in B3gnt5(-/-) B cells by flow cytometry and fluorescence microscopy. However, no difference in the amount of GM1 was observed by TLC-immunoblotting analysis. The GEM-stained puncta on the surface of B3gnt5(-/-) resting B cells were brighter and larger than those of WT cells. These results suggest that structural alteration of GEM occurs in B3gnt5(-/-) B cells. We next examined whether BCR signaling-related proteins, such as BCR, CD19, and the signaling molecule Lyn, had moved into or out of the GEM fraction. In B3gnt5(-/-) B cells, these molecules were enriched in the GEM fraction or adjacent fraction. Moreover, B3gnt5(-/-) B cells were more sensitive to the induction of intracellular phosphorylation signals on BCR stimulation and proliferated more vigorously than WT B cells. Together, these results suggest that lacto/neolacto-series GSLs play an important role in clustering of GEMs and tether-specific proteins, such as BCR, CD19, and related signaling molecules to the GEMs.